Residual prostate cancer cells after docetaxel therapy increase the tumorigenic potential via constitutive signaling of CXCR4, ERK1/2 and c-Myc.

Abstract

UNLABELLED:

Despite an increasing prevalence of patients with docetaxel-refractory prostate cancer, little is known about the tumor biology of the docetaxel-resistant residual tumor cells compared with primary tumor cells. In this study, tumorigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines (DRD, 1G7 and PC3DR) compared with parental cells (DU145 or PC3). Enhanced tumorigenic potential was conferred by oncogenic c-Myc, which was stabilized by constitutively activated ERK1/2 in DRD, 1G7, and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was upregulated in DRD, 1G7, and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilizing c-Myc. Furthermore, constitutive activation of CXCR4, ERK1/2, and c-Myc signaling was evident in clinical tissue samples from human patients with docetaxel-resistant prostate cancer. In DTX-resistant residual prostate cancer cells, the enhanced tumorigenic potential was reduced by ERK1/2 inhibition, or by AMD3100, a CXCR4 antagonist. Thus, docetaxel treatment constitutively activated the CXCR4, ERK1/2, and c-Myc signaling loop in docetaxel-resistant residual prostate cancer cells.

IMPLICATIONS:

Constitutive signaling pathways are viable therapeutic targets for residual prostate tumor cells following acquisition of docetaxel resistance.

• Authors: Koji Hatano, Souhei Yamaguchi, Keisuke Nimura, Kouki Murakami, Akira Nagahara, Kazutoshi Fujita, Motohide Uemura, Yasutomo Nakai, Mutsumi Tsuchiya, Masashi Nakayama, Norio Nonomura, Yasufumi Kaneda
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 9 Pg. 1088-100 (Sep 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23788635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• Benzylamines
• Cyclams
• Heterocyclic Compounds
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Receptors, CXCR4
• Taxoids
• Docetaxel
• plerixafor

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Benzylamines
• Carcinogenesis
• Cell Line, Tumor
• Cyclams
• Disease Models, Animal
• Docetaxel
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Heterocyclic Compounds (pharmacology)
• Humans
• MAP Kinase Signaling System
• Male
• Mice, Nude
• Mice, SCID
• Neoplasm, Residual (metabolism, pathology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Receptors, CXCR4 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Taxoids (therapeutic use)